I graduated in 1995 at the EMBL (European Molecular Biology Laboratory) in Heidelberg, Germany, after spending four years in the laboratory of Sara Courtneidge working on the the regulation and function of src-family tyrosine kinases. I then moved as a post-doc in the laboratory of George Thomas to work on regulation of protein synthesis and responses to inhibition of ribosome biogenesis, first in Switzeland at the FMI (Friedrich Miescher Institut) in Basel then in the USA at the University of Cincinnati, where I was a research associate. In 2011 I joined the Institut Necker Enfants Malades in Paris as a group leader after obtaining a permanent DR2 position of the Inserm (Institut national de la santé et de la recherche médicale).

Focus

Altered ribosome synthesis is associated with cancer and ribosomopathies. Our goal is to dissect responses to impaired ribosome synthesis, assess their role in ribosomopathies and the therapeutic potential in the tratment of tumors.

Introduction

The surge in ribosome biogenesis that ensues as cells undergo growth and proliferation is a major energy consuming process that employs a considerable amount of protein and RNA precursors. For this reason ribosome biogenesis is tightly regulated and alterations in its execution are associated with pathological conditions. Thus, excessive ribosome biogenesis is associated with cancer. Indeed potent oncogenes (MTOR; cMYC) drive ribosome synthesis and interestingly, pharmacological suppression of ribosome synthesis results in anti-proliferative and pro-apoptotic effects, in part dependent on the tumor suppressor p53, of therapeutic potential. On the other hand those same effects contribute to the pathogenesis of a class of congenital diseases known as ribosomopathies caused by impairment of ribosome synthesis, for which an implication of p53 has been clearly established. Targeting p53, a tumor suppressor, to treat these diseases is not a viable option. It would be therefore valuable to determine if transcriptional targets of p53 that do not play tumor suppressor-functions contribute to its pathogenic effects. In addition, apart from the documented effects on proliferation and survival linked to p53 up-regulation, there is little insight on other effects that could affect cellular homeostasis in concert with or independently of p53. The characterization of these responses may open novel avenues for the treatment of ribosomopathies and inform therapeutic strategies for the treatment of tumors.

Research objectives

Our goal is to obtain a comprehensive view of the effects of impairement of ribosome biogenesis on cellular homeostasis. For this we have undertaken a transcriptomic analysis on a system of inhibition of ribosome synthesis based on depletion of ribosomal proteins in cultured cells. Apart from the expected up-regulation of p53 targets this analysis has shown that impairement of ribosome synthesis causes changes in gene expression that suggest alterations in major cellular functions, affecting proteostasis and metabolism and resulting in altered sensitivity to stress signals. Interstingly these responses occur irrespective of p53 induction. In order to get insight into mechanisms of disease we also employ a model system of ribosomopatrhy consisting on inducible deletion in mice of the gene encoding the ribosomal protein eS6. In particular we are taking advantage of heterozygous deletion in cells of the bone marrow, that leads to an anaemia that recapitulates the features of Diamond-Blackfan anaemia (DBA), a ribosomopathy, in order to adress the implication of p53 targets, such as the cell cycle inhibitor p21. This same system will be useful to interrogate the involvement of other responses to impairement of ribosome synthesis as well as to model symptoms of ribosomopathies other than those affecting the erythron. It will then be important to determine the relevance for pathologies in humans of findings from these studies.

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Support(s)

HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

Legal mentions

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